CN1251987A - Dasage forms comprising separate portions of R- and S-enantiomers - Google Patents
Dasage forms comprising separate portions of R- and S-enantiomers Download PDFInfo
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- CN1251987A CN1251987A CN98804125.1A CN98804125A CN1251987A CN 1251987 A CN1251987 A CN 1251987A CN 98804125 A CN98804125 A CN 98804125A CN 1251987 A CN1251987 A CN 1251987A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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Abstract
A pharmaceutical dosage form comprises, in one portion thereof, a substantially single (+)-enantiomer of a chiral drug other than verapamil and, in another, separate portion thereof, a substantially single (-)-enantiomer of the drug wherein, in use, the different enantiomers are released at different rates from the dosage form. The dosage form is useful for administration of chiral drugs where both enantiomers have a valid pharmacological input, and where a clinical benefit may be realised by controlling the release rates of those enantiomers. Examples of such drugs include, in particular, tramadol and warfarin.
Description
The present invention relates to the discovery of the novel drugs dosage form of chiral drug.
The different enantiomer of some chiral drugs have different treatment characteristics and/or the mechanism of action and in some cases, it still needs to take together two kinds of enantiomer.But, when the pharmacokinetic properties of different enantiomer not simultaneously, for example because the difference of their speed of metabolism, after the beginning administration along with the ratio between the different enantiomer of the variation of time changes, this has caused the decline of efficacy of drugs.The actual ratio of enantiomer depends on many factors at any time, and if different dosage form different enantiomeric ratio are provided, it is complicated that the actual ratio of enantiomer may also be wanted.Now observed the effect of the different enantiomer of verapamil, for example referring to Longstreth, J.A.Clin.Pharmacol. (1993) 18 (second edition): 315-336 and Gupta etc., Eur.J.Pharm.Biopharm. (1996) 42 (1): 74-81.
According to the present invention, pharmaceutical dosage form contain mainly be chiral drug single (+)-enantiomer a part and mainly be the other separated portions of this medicine single (-)-enantiomer, rather than verapamil, wherein in use, different enantiomer discharge with different speed from this dosage form.
When human body during with the different enantiomer of different rates absorption, metabolism, distribution or secretion chiral drug, can during whole administration, be arranged to the first ratio that makes that keeps them to the rate of release from this dosage form ideally, or 50: 50 or be non-racemization ratio.By operating the administration of different enantiomer in such a way, make the existence of the required enantiomer of target organs is idealized, increase the clinical efficacy of whole administration process Chinese medicine thus.
The present invention also is useful for having different efficacies, different binding mode, different choice as the single enantiomer administration to receptor or enzyme or different toxic chiral drugs.
The present invention is to having side effect accordingly but a kind of chiral drug administration that this side effect exists only in two kinds of enantiomer of medicine also is useful.In this case, it is ideal that the enantiomer that causes side effect is had different release rates, although this will depend on the character of side effect.
Two kinds of enantiomer degree have effective pharmacology input and wherein realize that by the release rate of these enantiomer the example of the chiral drug of clinical advantages comprises warfarin, tramadol, mianserin, carvedilol, citalopram, dobutamine, aminoglutethimide, alfuzosin, celiprolol, cisapride, disopyramide, fenoldopam, flecainide, oxychloroquine, ifosfamide, labetalol, mexiletine, Propafenone, ftorafur, terazosin, thioctic acid, thiobarbiturate and zacopride.And preferred warfarin and tramadol, the best is a tramadol.
The present invention relates to any dosage form, thereby wherein two of chiral drug enantiomer can the difference that can realize different enantiomer isolating or at interval discharge physically.This separation or interval can be large-scale, for example different enantiomer is mixed in the separation dosage form of while or administration subsequently, promptly as a kit, perhaps different Separation of Enantiomers are small-scale, for example different enantiomer are put in the same dosage form, although their physical separation is well-mixed, perhaps sometimes be middle two parts.
In the content of this application, almost be that single enantiomer generally refers to a kind of enantiomer above another enantiomer at least 70% (weight), and preferred above at least 80%, the best is 90% or higher.Further, the non-racemization ratio of enantiomer refers to and has two kinds of enantiomer, and the amount of perhaps (-)-enantiomer surpasses (+)-enantiomer, and is perhaps opposite.
Can realize many release profiles of the different enantiomer of chiral drug by dosage form of the present invention.For example, can design a kind of dosage form makes a kind of enantiomer middling speed discharge and another kind of enantiomer continues or sustained release.In this case, middling speed discharges us and refers at horse back after the dosage form administration or after an of short duration delay, is no more than the release that corresponding enantiomer took place in 5 to 10 minutes usually, and reach 1 to 2 hour lasting usually one period.Continue or sustained release general we refer to after this dosage form administration, postpone the release at least 1 hour of corresponding enantiomer and often longer, for example 2 hours or more hours.During whole treatment, lasting or sustained release can be constant or variable.
Dosage form of the present invention can be designed as release a kind of in the enantiomer faster than another kind, and perhaps before another kind, this depends on the state of an illness of being treated or patient's type.It is desirable to particular time for example a day at least 8 hours, preferred one day at least 12 hours, kept the fixed ratio of enantiomer separation in best one day 24 hours in target tissue.The ratio that is kept can be 50: 50, or a kind of non-racemization ratio, and the amount of wherein (+)-enantiomer is greater than the amount of (-)-enantiomer, and is perhaps opposite.
During whole treatment, perhaps in the part at least during this period, other selection can change the ratio of two kinds of enantiomer.For example, can arrange the releases a kind of or two kinds in the enantiomer to change, thereby make the corresponding proportion of (+)-enantiomer or the corresponding proportion of (-)-enantiomer increase or reduce along with the time.For example by each enantiomer being used many different release coatings can realize the latter.
As mentioned above, the present invention has special purposes aspect the administration of tramadol and warfarin.Tramadol is formulated as racemoid as the efficient analgesic with OPIOIDS characteristic.The effect of this racemoid and single enantiomer and safety have been used and have been used intravenous control patient analgesic random double blind test to carry out studying that (referring to Grond, s is etc., pain (1995) 62 (3): 313-320) to gynecologic patient.Although demonstrate stronger effect at (+)-tramadol aspect the generation pain relieving, its has also produced more nausea and vomiting simultaneously.Because this racemoid has stronger effect and littler than the side effect of (+)-tramadol than (-)-tramadol, author's this racemoid of reaching a conclusion is more suitable for clinical practice.In another one test, demonstrated between each enantiomer of tramadol, exist complementary and synergistic anti-nociception react (referring to Raffa, R.B. etc., J Pharmacol.Exp.Ther. (1993) 267 (1): 331-340).This enantiomer to opioid receptor with suppress serotonin take in again and the absorption again of norepinephrine has different effects.So showing two kinds of enantiomer of tramadol all works to analgesic effect.Therefore, might make that to control the administration of each enantiomer with different rates easier, can cause like this even more useful pain relieving and do not have other side effect by dosage form that the present invention comprised.
A kind of preferred dosage form of tramadol administration is a kind of such dosage form, and wherein (-)-tramadol is that middling speed releasing pattern and (+)-tramadol are for continuing or the sustained release form.In this case, can control the rate of release of (+)-tramadol in such a way, promptly reduce the nauseating and/or dizzy adverse side effect of thinking relevant with this enantiomer.
Concerning the situation of anticoagulant warfarin, current is it to be formulated as racemoid be used for clinical use, (S)-(-)-and (R)-(+)-enantiomer all has the activity of needed hypoprothrombinemia, wherein (S)-warfarin more effective (referring to, Hyneck, M. etc., drug design and synthetic in chirality (1990), the 17-18 page or leaf is edited by C.Brown, and the academic press, London publishes).But, promptly before required blood coagulation resisting function onset, postpone to make the use of warfarin become complicated in several days as racemoid with this form.Like this, in case the treatment beginning, thus must carefully monitor the balance that reaches between dosage deficiency and the administration excess; The administration excess can cause hemorrhage and fatal sometimes.This effect is that each enantiomer by the warfarin that albumin bound is had different affinitys produces, and each enantiomer is metabolic by different passages, and these passages will influence corresponding clearance rate conversely.So the administration of the unitary agent of each Separation of Enantiomers preparation or each Chiral Separation can realize the therapeutic scheme of better control.
As oral cavity, rectum, percutaneous, nasal cavity, lung and the injection (subcutaneous or vein), can design many dissimilar dosage forms concerning by all means.
Applicant's pending application WO 97/33570 has described a kind of dosage form, and it is the single enantiomer that discharges verapamil with different rates, and the arbitrary medicine in the said medicine can use a kind of in these dosage forms.
For example, one type dosage form contains capsule, comprises two types the multiparticulates with different rates of release in this capsule, a kind ofly contains (+)-enantiomer and another contains (-)-enantiomer.Any preparation in the enough conventional methods of this multiparticulates energy, these methods comprise extruding nodularization method, high speed shear granulation, nonpareil granule method etc.For example substrate (corrode diffusion), coating or infiltration can realize discharging the speed of different enantiomer from multiparticulates to use any conventional sustained release mechanism.Such dosage form is suitable for oral and rectum uses.
Another kind of dosage form contains two kinds of sheets, and promptly as a kind of product (kit) of combination, a kind of comprises (+)-enantiomer and another sheet comprises (-)-enantiomer, and two kinds of sheets have different rates of release.Use conventional control release technic can reach needed effect.For example, can use two kinds to have the different sheets that discharge coating or substrate, perhaps two kinds have the osmotic pump tablet that difference pumps into speed.Insert administration simultaneously in the capsule these sheets administration successively or with them then.
Another class dosage form contains osmotic pump tablet, and this sheet contains different two parts, is generally two-layerly, and a part comprises and pump into (+)-enantiomer with a kind of speed, and a part comprises and pumps into (-)-enantiomer with another speed in addition.
Another class dosage form contains a kind of double-layer tablet, one deck comprise (+)-enantiomer and in addition one deck comprise (-)-enantiomer, each corresponding enantiomer two-layer has different rates of release.Conventional control release technic can be used for realizing required effect.
An example of double-layer tablet can contain (-)-tramadol at skin and make initial treatment, and discharging (+)-tramadol from the sheet heart provides lasting treatment.An other example of double-layer tablet is to treat to start with at outer field (S)-warfarin, and sheet (R)-tramadol in the heart is as continued treatment.Thereby the different weight percentage that can use each enantiomer in different tablets is to individual titration dosage.
Another kind of dosage form comprises the coating tabletting, and wherein label comprises (+)-and (-)-enantiomer, and the shell around the sheet heart comprises another (+)-and (-)-enantiomer, and the sheet heart has different rates of release with shell concerning each enantiomer.
Another kind of dosage form comprises is close to the paster that patient skin is placed, and this paster divides two kinds of different parts, a part comprise (+)-enantiomer and in addition a part comprise (-)-enantiomer, two parts have different rates of release concerning each enantiomer.Perhaps, use two isolating pasters, promptly as a kind of combination product (kit), a kind of paster comprises (+)-enantiomer and another kind of paster comprises (-)-enantiomer, and two kinds of pasters have different rates of release.
Another class dosage form comprises the polymer implant, and it comprises two different parts, and a part comprises (+)-enantiomer and another part comprises (-)-enantiomer, and two parts have different rates of release concerning each enantiomer.Perhaps, use two kinds of isolating polymer implants, promptly as a kind of product (kit) of combination, a kind of implant comprises (+)-enantiomer and another kind of implant comprises (-)-enantiomer, and two kinds of implants have different rates of release.
Another kind of dosage form comprises aerosol, the microgranule that it divides two classes to have different rates of release, and a class comprises (+)-enantiomer and an other class comprises (-)-enantiomer.Perhaps, use two kinds of isolating aerosols, a kind of one of enantiomer that comprises, promptly as a kind of combination product (kit), the microgranule of every kind of aerosol has different rates of release.
Another class dosage form can be to pass through drug administration by injection.In this class dosage form, can realize the different rates of release of different enantiomer by liposome or microparticle.
In the present invention, when when effective, providing them two kinds of enantiomer separate administration with a kind of harmless form of patient to expection.If the form with salt provides them, preferred two kinds of salt should all be stablized and be non-hygroscopic.
Dosage form of the present invention can be used in these diseases of treatment, promptly takes chiral drug usually, and particularly making the patient tend to disadvantageous side effect or patient can emit certain danger because of being exposed to disadvantageous side effect.
Illustrate in greater detail the present invention by the following example now.Embodiment
Be to use the logical testing equipment (Instron floor model, Instron Limited, High Wycombe, United Kingdom) of a Daepori with 1mm/ minute pressure speed below, the sheet of 200MPa is pressed and the plane punching out of 8mm is equipped with tablet.
Use the disintegrative of this sheet of aquametry of 37 ℃ ± 0.2K according to BP at disintegrate tester (Erweka GmbH, Heusenstam Germany).Using USP XXIII splash bar method (drug test, Germany, hamburger) is that 100rpm uses the distilled water of 1000ml to measure the solubility curve of this sheet at 37 ℃ ± 0.5K and splash bar speed.Measure medicine (+)-or the stripping quantity of (-)-tranadol hydrochloride with the online UV (Phillips PU8620, Hamburg, Germany) of 220nm wavelength.
In the accompanying drawings, Fig. 4 ■ represent (+)-tramadol salts hydrochlorate and
Expression (-)-tramadol salts hydrochlorate.Embodiment 1
With 200MPa sheet pressure handle 50.0mg (+)-or (-)-tramadol salts hydrochlorate, 46.5mg microcrystalline Cellulose sodium, the mixed-powder of 3.0mg cross-linked carboxymethyl cellulose sodium and 0.5mg magnesium stearate is made the tablet that middling speed discharges.Monitoring disintegrate in 30 minutes.
Fig. 1 has shown the concentration of each enantiomer in the solvent with the y-axle, has described the drug release of middling speed releasing piece.Viewed solubility curve has been guaranteed the quick medicament availability of this medicine.Embodiment 2
With 200MPa sheet pressure handle 50.00mg (+)-or the mixed-powder of (-)-tramadol salts hydrochlorate, 119.15mg hydroxypropyl emthylcellulose (HPMC) and 0.85mg magnesium stearate make the tablet of sustained release.During 7 hours, monitor disintegrate.
In Fig. 2, each enantiomer concentration in the solvent that shows with the y-axle, solubility curve and the percent that discharges of Fig. 3 Chinese medicine drug release of having described this sustained release tablet.Realized 12 hours sustained release with said preparation.After 6 hours, the release of (-)-enantiomer is little faster than (+)-enantiomer, reached nearly 100% drug release at 12 hours, and only 86% (+)-enantiomer discharges after 12 hours.Below 6 hours, the drug release curve of two kinds of enantiomer is closely similar.Embodiment 3
Form a kind of sustained release layer with the mixed-powder before the compacting among the sheet pressure handle embodiment 2 of 20MPa and prepare bilayer tablet.Then, mixed-powder among the embodiment 1 that contains the enantiomer opposite with tranadol hydrochloride enantiomer in the sustained release layer is filled out at the sustained release laminar surface, be pressed into whole tablet with the sheet of 200MPa.
(eluant is 90% pentane with a Chiralpak AD post, 9.99% isopropyl alcohol, 0.01% diethylamine) obtain the solubility curve of each layer of double-layer tablet by analysis to the chirality HPLC of tramadol free alkali, wherein (+)-tramadol has 4.5 minutes retention time and (-)-tramadol has 5.6 minutes retention time on Chiralpak AD post, and described the solubility curve of each layer in Fig. 4, wherein the y-axle is represented the concentration of each enantiomer in the solvent.
The amount by changing used excipient and only at the shorter release profiles that in present case, just can realize the sustained release layer by the amount that reduces HPMC.In addition, the dosage of Zeng Jiaing if desired then can increase the diameter of tablet.
Claims (35)
1. pharmaceutical dosage form, it contains single (+)-enantiomer rather than the verapamil that some is a chiral drug, and in other separated portions, is single (-)-enantiomer of this medicine, wherein in use, different enantiomer are to discharge from this dosage form with different speed.
2. according to the dosage form of claim 1, wherein said chiral drug is any medicine, and the different enantiomer of this medicine can be by human body with different speed absorption, metabolism, distribution or secretion.
3. according to the dosage form of claim 1 or 2, chiral drug wherein is any medicine, and the different enantiomer of this medicine all has different effects or different binding modes.
4. according to the dosage form of claim 1 or 2, chiral drug wherein is anyly to have disadvantageous side effect and this side effect and be present in a kind of medicine in two kinds of enantiomer.
5. according to the dosage form of aforementioned claim, wherein select the release rate of different enantiomer to make target tissue obtain the almost fixed ratio of these enantiomer at least at one day 8 hours.
6. according to the dosage form of claim 5, wherein the ratio of enantiomer approximately is 50: 50 in target tissue.
7. according to the dosage form of claim 5, wherein the ratio of enantiomer is the ratio of non-racemization in target tissue, i.e. it is excessive that (+)-enantiomer is compared with (-)-enantiomer.
8. according to the dosage form of claim 5, wherein the ratio at the enantiomer of target tissue is the ratio of non-racemization, i.e. it is excessive that (-)-enantiomer is compared with (+)-enantiomer.
9. according to the dosage form of claim 1, wherein the release rate of at least one enantiomer changes in time.
10. according to the dosage form of claim 9, the release rate of wherein (+)-enantiomer increased or reduces along with the time.
11. according to the dosage form of claim 1, the release rate of wherein (-)-enantiomer increased or reduces along with the time.
12. according to the dosage form of claim 1, the release of wherein (+)-enantiomer is faster than the release of (-)-enantiomer.
13. according to the dosage form of claim 1, the release of wherein (-)-enantiomer is faster than the release of (+)-enantiomer.
14. according to the dosage form of aforementioned arbitrary claim, it comprises capsule, capsule contains many first granule and many second granules that contain (-)-enantiomer that contain (+)-enantiomer, and first and second granules have the different release rate of each enantiomer.
15. according to arbitrary dosage form of claim 1-13, it comprises the first kind of sheet that contains (+)-enantiomer and contain second kind of sheet of (-)-enantiomer, first kind has the different release rate of each enantiomer with second kind of sheet.
16., wherein first kind and second kind of sheet are wrapped in the capsule according to the dosage form of claim 15.
17. according to arbitrary dosage form of claim 1-13, it contains the sheet of osmotic pumps, this sheet has the first of containing (+)-enantiomer and contains the second portion of (-)-enantiomer, and wherein the difference of first and second parts with each enantiomer pumps rate.
Another layer contains (-)-enantiomer, two-layer different release rates with each enantiomer 18. according to arbitrary dosage form of claim 1-13, it contains double-layer tablet, and one deck contains (+)-enantiomer.
19. according to arbitrary dosage form of claim 1-13, it contains the coating tabletting, this sheet label contains (+)-and one of (-)-enantiomer, and the sheet shell contains (+)-and the another kind of (-)-enantiomer around the label.
20. arbitrary dosage form according to claim 1-13, it contains the paster of being close to patient skin, this paster has the first of containing (+)-enantiomer and contains the second portion of (-)-enantiomer, and wherein first and second parts have the different release rates of each enantiomer.
21. according to arbitrary dosage form of claim 1-13, it contains two kinds of pasters, two pasters all are close to patient skin, and paster contains (+)-enantiomer and another paster contains (-)-enantiomer, and two kinds of pasters have different release rates.
22. according to arbitrary dosage form of claim 1-13, it contains polymeric implant, this implant has the first of containing (+)-enantiomer and contains the second portion of (-)-enantiomer, and wherein first and second parts have the different release rates of each enantiomer.
23. according to arbitrary dosage form of claim 1-13, it contains two kinds of polymeric implants, implant contains (+)-enantiomer and another implant contains (-)-enantiomer, and two kinds of implants have different release rates.
24. according to arbitrary dosage form of claim 1-13, it contains a kind of two groups of aerosols with microparticle of different release rates that comprise, one group contain (+)-enantiomer and other one group contain (-)-enantiomer.
25. arbitrary dosage form according to claim 1-13, it contains two kinds of aerosols, a kind of is to contain the microparticle of (+)-enantiomer and another is the microparticle that contains (-)-enantiomer, and the microparticle in two kinds of aerosols has the different release rates of each enantiomer.
26. according to the dosage form of the arbitrary claim in front, wherein chiral drug is selected from warfarin, tramadol, mianserin, carvedilol, citalopram, dobutamine and Aminoglutethimide.
27. according to the dosage form of claim 26, chiral drug wherein is a warfarin.
28. according to the dosage form of claim 26, chiral drug wherein is a tramadol.
29. according to the dosage form of claim 28, wherein (-)-tramadol is a middling speed releasing pattern and (+)-tramadol is a sustained release form.
30. according to the dosage form of claim 28 or 29, it is a kind of double-layer tablet, skin contains (-)-tramadol, and label contains (+)-tramadol.
31. according to arbitrary dosage form of claim 1 to 25, wherein chiral drug is selected from alfuzosin, celiprolol, cisapride, norpace (disopyramide), fenoldopam, flecainide, oxychloroquine, ifosfamide, labetalol, mexiletine, Propafenone, ftorafur, terazosin, thioctic acid, thiobarbiturate and zacopride.
32. according to arbitrary dosage form of claim 1-25, chiral drug wherein is any medicine with different enantiomer of different choice.
33. according to arbitrary dosage form of claim 1-25, chiral drug wherein is any medicine with different toxic different enantiomer.
34. according to arbitrary dosage form of claim 1-27 and 31-33, one of them enantiomer is a middling speed releasing pattern and the another one enantiomer is a sustained release form.
35. the almost single enantiomer of chiral drug is in the purposes of preparation as the defined dosage form of preceding arbitrary claim, this dosage form is used for the treatment of usually the disease with the racemization form administration, patient or tend to disadvantageous side effect or emit danger because of being exposed to disadvantageous side effect.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9704978.7 | 1997-03-11 | ||
| GBGB9704978.7A GB9704978D0 (en) | 1997-03-11 | 1997-03-11 | Dosage forms |
| GB9719261.1 | 1997-09-10 | ||
| GBGB9719261.1A GB9719261D0 (en) | 1997-09-10 | 1997-09-10 | Dosage forms |
| US09/038,873 US6056968A (en) | 1997-03-11 | 1998-03-11 | Pharmaceutical drug dosage forms providing different release rates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1251987A true CN1251987A (en) | 2000-05-03 |
Family
ID=27268767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98804125.1A Pending CN1251987A (en) | 1997-03-11 | 1998-03-11 | Dasage forms comprising separate portions of R- and S-enantiomers |
Country Status (15)
| Country | Link |
|---|---|
| US (2) | US6056968A (en) |
| EP (1) | EP0969818B1 (en) |
| JP (1) | JP2001514651A (en) |
| CN (1) | CN1251987A (en) |
| AT (1) | ATE275394T1 (en) |
| AU (1) | AU741821B2 (en) |
| BR (1) | BR9808325A (en) |
| CA (1) | CA2285407C (en) |
| DE (1) | DE69826113T2 (en) |
| ES (1) | ES2227814T3 (en) |
| HU (1) | HUP0000759A3 (en) |
| IL (1) | IL131713A (en) |
| NO (1) | NO994412L (en) |
| PL (1) | PL335619A1 (en) |
| WO (1) | WO1998040053A1 (en) |
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| DE60107393T2 (en) | 2000-03-01 | 2005-12-01 | Euro-Celtique S.A. | USE OF TRAMADOL FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF FUNCTIONAL GASTROINTESTINAL HOSPITALITY |
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| US6562871B1 (en) * | 2000-11-06 | 2003-05-13 | Boehringer Ingelheim Pharmaceuticals, Inc. | Dry granulation of pharmaceutical formulation comprising mexiletine |
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| IN191028B (en) * | 2001-05-17 | 2003-09-13 | Sun Pharmaceutical Ind Ltd | |
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| US20050143350A1 (en) * | 2003-11-19 | 2005-06-30 | Seed John C. | Combination drug therapy to treat obesity |
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| JP5072364B2 (en) | 2003-11-25 | 2012-11-14 | スミスクライン ビーチャム （コーク） リミテッド | Carvedilol free base, carvedilol salt, anhydrous form or solvate thereof, corresponding pharmaceutical composition, controlled release formulation and treatment or delivery method |
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| KR101655455B1 (en) | 2005-09-09 | 2016-09-07 | 안젤리니 라보팜 엘엘씨 | Trazodone composition for once a day administration |
| EP1976488A4 (en) * | 2006-01-12 | 2010-02-10 | Wockhardt Ltd | Sustained release compositions of alfuzosin |
| PL2002828T3 (en) * | 2006-03-30 | 2019-11-29 | Nippon Zoki Pharmaceutical Co | Solid pharmaceutical preparation |
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| US4818541A (en) * | 1987-08-19 | 1989-04-04 | Schering Corporation | Transdermal delivery of enantiomers of phenylpropanolamine |
| US5145866A (en) * | 1991-04-22 | 1992-09-08 | Hoechst-Roussel Pharmaceuticals Incorporated | Method of treating anxiety with the aid of r(+)-3-amino-1-hydroxy-pyrrolidin-2-one |
| US5204116A (en) * | 1991-05-01 | 1993-04-20 | Alza Corporation | Dosage form providing immediate therapy followed by prolonged therapy |
| IL119660A (en) * | 1993-05-10 | 2002-09-12 | Euro Celtique Sa | Controlled release formulation comprising tramadol |
| DE4319438C1 (en) * | 1993-06-11 | 1994-06-01 | Gerd Dr Dr Geislinger | Analgesic and/or antiinflammatory medicaments - contg. sepd enantiomers of ketoprofen |
| GB9412689D0 (en) * | 1994-06-23 | 1994-08-10 | Chiroscience Ltd | Cytotoxic agent and its use |
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1998
- 1998-03-11 DE DE69826113T patent/DE69826113T2/en not_active Expired - Fee Related
- 1998-03-11 CA CA002285407A patent/CA2285407C/en not_active Expired - Fee Related
- 1998-03-11 EP EP98910863A patent/EP0969818B1/en not_active Expired - Lifetime
- 1998-03-11 ES ES98910863T patent/ES2227814T3/en not_active Expired - Lifetime
- 1998-03-11 BR BR9808325-2A patent/BR9808325A/en not_active IP Right Cessation
- 1998-03-11 WO PCT/GB1998/000726 patent/WO1998040053A1/en not_active Application Discontinuation
- 1998-03-11 CN CN98804125.1A patent/CN1251987A/en active Pending
- 1998-03-11 AT AT98910863T patent/ATE275394T1/en not_active IP Right Cessation
- 1998-03-11 AU AU65089/98A patent/AU741821B2/en not_active Ceased
- 1998-03-11 HU HU0000759A patent/HUP0000759A3/en unknown
- 1998-03-11 JP JP53935798A patent/JP2001514651A/en not_active Ceased
- 1998-03-11 US US09/038,873 patent/US6056968A/en not_active Expired - Fee Related
- 1998-03-11 IL IL13171398A patent/IL131713A/en not_active IP Right Cessation
- 1998-03-11 PL PL98335619A patent/PL335619A1/en unknown
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1999
- 1999-09-10 NO NO994412A patent/NO994412L/en not_active Application Discontinuation
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2000
- 2000-01-05 US US09/478,177 patent/US6221394B1/en not_active Expired - Fee Related
Also Published As
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|---|---|
| JP2001514651A (en) | 2001-09-11 |
| NO994412L (en) | 1999-10-20 |
| AU6508998A (en) | 1998-09-29 |
| HUP0000759A3 (en) | 2000-11-28 |
| DE69826113T2 (en) | 2005-01-20 |
| WO1998040053A1 (en) | 1998-09-17 |
| EP0969818B1 (en) | 2004-09-08 |
| US6221394B1 (en) | 2001-04-24 |
| US6056968A (en) | 2000-05-02 |
| CA2285407A1 (en) | 1998-09-17 |
| CA2285407C (en) | 2006-08-01 |
| ATE275394T1 (en) | 2004-09-15 |
| IL131713A0 (en) | 2001-03-19 |
| BR9808325A (en) | 2000-05-16 |
| NO994412D0 (en) | 1999-09-10 |
| EP0969818A1 (en) | 2000-01-12 |
| HUP0000759A2 (en) | 2000-10-28 |
| DE69826113D1 (en) | 2004-10-14 |
| ES2227814T3 (en) | 2005-04-01 |
| PL335619A1 (en) | 2000-05-08 |
| IL131713A (en) | 2004-08-31 |
| AU741821B2 (en) | 2001-12-13 |
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